Methods of administering antihistamines

ABSTRACT

Methods of using combinations of antihistamines by administering an attenuated dosage amount of a first generation antihistamine for a quick onset concomitantly with a maintenance dosage amount of a second or third generation antihistamine are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/527,182 filed Aug. 25, 2011, which is hereby incorporated byreference in its entirety.

BACKGROUND

Antihistamines find wide use in treating allergies by blocking thebinding of histamine to histamine H₁-receptors and thereby suppressingsymptoms such as a runny nose or watery eyes. So-called first generationantihistamines were developed that provided excellent reduction in thesymptoms of rhinitis, however many of these early compounds induced asedative effect in the patient, as they are nonselective for theH₁-receptor. Depending upon the time of day of administering aconventional recommended dose of a first generation antihistamine, thesedative effect may or may not be desired. For example, sedation wouldnot be desired during the day while most patients need to be active andfully functional, often requiring awareness for daily activities such asworking or driving a car.

Second and third generation antihistamines were subsequently designed toavoid the sedative effect exhibited in the earlier generation ofcompounds. These compounds were developed such that they do not crossthe blood brain barrier and thus are selective for peripheral H₁receptors outside of the central nervous system, thereby exhibiting areduced sedative effect.

Although the second and third generation antihistamines avoid thesedative effect of the first generation antihistamines, they exhibit alag from the time of administration to time when the patient starts toexperience symptomatic relief. Several second generation antihistamines,such as terfenadine, astemizole, cetirizine, and loratadine, exhibit alag time of several hours before onset of action (See Annals of Allergy,Asthma, & Immunology (1997), 79, 163-172).

Thus, there remains a need in the art for methods of administeringantihistamines that provides rapid, sustained, and improved therapeuticeffect while at the same time avoiding a sedative effect such that theadministration can occur regardless of the time of day.

SUMMARY

In one embodiment, a method of orally administering an antihistaminecombination comprises concomitantly administering to a patient in needof antihistamine treatment a first generation antihistamine in anattenuated dosage amount to provide a quick onset of action wherein thepatient experiences substantially no sedative effect; and a second orthird generation antihistamine in a maintenance dosage amount to providecontinued antihistaminic effect.

In another embodiment, a method of treating a patient in need oftreatment of an allergic reaction comprises orally administering to apatient a first generation antihistamine in an attenuated dose toprovide a quick onset of action wherein the patient experiencessubstantially no sedative effect; and concomitantly administering orallywith the first generation antihistamine, a second generationantihistamine in a maintenance dose to provide continued antihistaminiceffect.

In yet another embodiment, a method of improving the efficacy of anantihistamine comprises administering to a patient in need ofantihistamine treatment a synergistic combination of a first generationantihistamine in an attenuated dosage amount to provide a quick onset ofaction wherein the patient experiences substantially no sedative effect;and a second or third generation antihistamine in a maintenance dosageamount to provide continued antihistaminic effect.

These and other embodiments, advantages and features of the presentinvention become clear when detailed description and examples areprovided in subsequent sections.

DETAILED DESCRIPTION

Disclosed herein are methods of using a combination of antihistamines byadministering an attenuated dosage amount of a first antihistamine thatis a first generation antihistamine to provide a quick onset oftherapeutic action followed by a maintenance dosage amount of a secondantihistamine that is a second or third generation antihistamine. Thecombination provides quick onset and improves the efficacy of theantihistamines as the two act synergistically with each other. Themethod can be carried out without regard to the time of day as the levelof first antihistamine will not induce a sedative effect or there willbe substantially no sedative effect, but rather will provide earlytherapeutic effect during the lag time a patient may experience from thetime of administration of a second or third generation antihistamine towhen the patient experiences symptomatic relief. For example,diphenhydramine, a first generation antihistamine, provides therapeuticeffect within 15 to 30 minutes after administration, while it may takeup to an hour or more for a patient to experience relief of symptomsusing fexofenadine, as second generation antihistamine.

As used herein, “substantially no sedative effect” means the patientexperiences such a minor sedative effect that it would not impair thepatient's ability to operate machinery or automobiles or perform othermental or physical tasks requiring a high level of concentration.

The attenuated dosage amount of the first generation antihistamine isselected to avoid a sedative effect while at the same time providingadequate prophylactic and symptomatic treatment of seasonal or perennialallergic rhinitis, vasomotor rhinitis, or other respiratory allergiesfor the first 1-2 hours after dosage administration. In one embodiment,the attenuated dosage amount of the first antihistamine is about 10 toabout 96% of the conventional recommended dosage amount of the firstgeneration antihistamine when used alone, specifically about 25 to about80%, more specifically about 40 to about 65%, and yet more specificallyabout 50 to about 55% of the conventional recommended dosage amount. Forexample, a conventional recommended adult dose of diphenhydraminehydrochloride administered on its own is 25 milligrams (mg) to 50 mg. Anattenuated dose for the present methods and compositions can be about 10to about 23 mg when used in combination with a second generationantihistamine. Other examples are provided in the table below.

Conventional recommended dose Dose range for Name (adult) combination1st Chlorpheneramine 2 mg to 4 mg 0.5 mg to 1.8 mg* genera- Maleate tionDiphenhydramine 25 mg to 50 mg 10 mg to 23 mg* HCl Doxylamine 6.25 mg to12.5 mg 2 mg to 6 mg* Succinate 2nd Cetirizine HCl 10 mg, 1 mg/ml 10 mg,1 mg/ml genera- Loratadine 10 mg, 1 mg/ml 10 mg, 1 mg/ml tionFexofenadine HCl 60 mg, 180 mg, 60 mg, 180 mg, 30 mg/5 ml 30 mg/5 ml*Less than the conventional recommended dose.

The maintenance dosage amount of the second antihistamine, that is thesecond or third generation antihistamine, can be about 90 to 100% of theconventional recommended dosage amount, specifically 100%. Exemplaryrecommended dosage amounts are provided in the table above.

In one embodiment, a method of orally administering an antihistaminecombination comprises concomitantly administering to a patient in needof antihistamine treatment a first generation antihistamine in anattenuated dosage amount to provide a quick onset of action whileavoiding a sedative effect; and a second or third generationantihistamine in a maintenance dosage amount to provide continuedantihistaminic effect. As used herein, “concomitantly administering”means the first generation and second/third generation antihistamine areadministered simultaneously, or within fifteen minutes of one another,specifically within ten minutes, and more specifically within fiveminutes of one another.

In another embodiment, a method of using an antihistamine combination totreat a patient in need thereof comprises concomitantly administering toa patient in need of antihistamine treatment a first generationantihistamine in an attenuated dosage amount to provide a quick onset ofaction while avoiding a sedative effect; and a second generationantihistamine in a maintenance dosage amount to provide continuedantihistaminic effect.

In yet another embodiment, a method of treating a patient with anantihistamine combination comprises orally administering an attenuateddosage amount of a first generation antihistamine suitable for treatmentof seasonal or perennial allergic rhinitis, vasomotor rhinitis, or otherrespiratory allergy to the patient who is concomitantly receivingadministration of a second generation antihistamine, wherein theattenuated dosage amount of first generation antihistamine is reducedcompared to the conventional recommended daily dosage amount of thefirst generation antihistamine for treatment of seasonal or perennialallergic rhinitis, vasomotor rhinitis, or other respiratory allergy inthe patient. In one embodiment, the attenuated dosage amount of thefirst antihistamine is about 10 to about 96% of the conventionalrecommended daily dosage amount of the first generation antihistaminewhen used alone, specifically about 25 to about 80%, more specificallyabout 40 to about 65%, and yet more specifically about 50 to about 55%of the conventional recommended daily dosage amount.

In yet another embodiment, a method of using an antihistaminecombination to treat a patient suffering from a condition treatable withan antihistamine comprises concomitantly administering to a patient inneed of antihistamine treatment a first generation antihistamine in anattenuated dosage amount to provide a quick onset of action whileavoiding a sedative effect; and a second generation antihistamine in amaintenance dosage amount to provide continued antihistaminic effect.

Exemplary first generation antihistamines include brompheniramine,buclizine, chlorpheniramine, cinnarizine, clemastine, cyclizine,cyproheptadine, diphenhydramine, diphenylpyraline, doxylamine,meclozine, pheniramine, promethazine, triprolidine, a pharmaceuticallyacceptable salt thereof, or a combination thereof; specificallychlorpheneramine maleate, diphenhydramine hydrochloride, doxylaminesuccinate, or a combination thereof.

Exemplary second and third generation antihistamines includeacrivastine, astemizole, cetirizine, desloratadine, fexofenadine,levocetirizine, loratadine, mizolastine, terfenadine, a pharmaceuticallyacceptable salt thereof, or a combination thereof; specificallycetirizine hydrochloride, fexofenadine hydrochloride, loratidine, or acombination thereof.

“Pharmaceutically acceptable salt” includes derivatives of the activeagent, wherein the active agent is modified by making acid or baseaddition salts thereof, and further refers to pharmaceuticallyacceptable solvates, including hydrates, crystalline forms,non-crystalline forms, and polymorphs, of such salts. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid addition salts of basic residues such as amines;alkali or organic addition salts of acidic residues; and the like, or acombinations thereof. The pharmaceutically acceptable salts includesalts and the quaternary ammonium salts of the active agent. Forexample, acid salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric andthe like; other acceptable inorganic salts include metal salts such assodium salt, potassium salt, cesium salt, and the like; and alkalineearth metal salts, such as calcium salt, magnesium salt, and the like,or a combination thereof. Pharmaceutically acceptable organic saltsincludes salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic,fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,isethionic, HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like; organicamine salts such as triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, and the like; and amino acid saltssuch as arginate, asparginate, glutamate, and the like; or a combinationthereof.

The first and second antihistamine can be formulated as a single dosageform or formulated as separate, independent dosage forms. A “dosageform” means a unit of administration of an active agent. The firstantihistamine is generally formulated for immediate-release, while thesecond antihistamine can be immediate-release or controlled-release.

The antihistamines can be formulated for oral or buccal administrationas a solid, liquid, or semisolid. “Oral dosage form” is meant to includea unit dosage form for oral administration. Exemplary solid oral andbuccal dosage forms include tablets, capsules, pellets, films, and thelike. Exemplary oral liquid dosage forms include solutions, suspensions,emulsions, and the like.

By “immediate-release” is meant a conventional or non-modified releasein which greater then or equal to about 75% of the active agent isreleased within two hours of administration, specifically within onehour of administration, yet more specifically within 30 minutes ofadministration.

By “controlled-release” is meant a dosage form in which the release ofthe active agent is controlled or modified over a period of time, anddoes not include immediate-release. Controlled can mean, for example,extended/sustained-, delayed- or pulsed-release at a particular time.

Liquid Dosage Forms

The liquid dosage forms generally include the first and second/thirdgeneration antihistamines and a liquid carrier. Additional optionalingredients include a suspending agent, a sweetener, a flavoring agent,a preservative, a pH adjusting agent, a colorant, or a combinationthereof.

The first and second/third generation antihistamines can be present inthe liquid composition in free form or in the form of a coated oruncoated granule, microtablet, pellet (as used herein “pellet” means aspherical granule prepared by extrusion and spheronization, and isequivalent to bead, spheroid, and microsphere), particle, or othermultiparticulate system. The coating can include film forming coating, ataste-masking coating, a controlled-release coating, and the like.

The liquid carrier can be water; glycerin; propylene glycol; a lowerpolyethylene glycol (e.g., polyethylene glycol 200, polyethylene glycol300, polyethylene glycol 400, polyethylene glycol 540, polyethyleneglycol 600, and the like); ethanol; propylene carbonate; or acombination thereof.

The liquid carrier can be present in the liquid composition in an amountof about 30 to about 98 weight percent (wt %) based on the total weightof the liquid composition, specifically about 40 to about 90 wt %, morespecifically about 50 to about 80 wt %, and yet more specifically about60 to about 70 wt %.

The suspending agent can be a carbomer, a cellulose derivative such aspowdered cellulose, methylcellulose, a hydroxyl alkyl cellulose such ashydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropylmethylcellulose, carboxy methyl cellulose calcium, carboxy methylcellulose sodium, polyvinylpyrrolidone; a natural gum such as gumacacia, carrageenan, sodium alginate, gellam gum, gum ghatti, guar gum,locust bean gum, tragacanth, xanthan gum; or a combination thereof.

A sweetener can be included in the liquid composition to make thecomposition palatable and more pleasing to the patient and to mask thetaste of the antihistamines. Exemplary sweeteners include sugar alcohols(or polyols), such as glycerol, sorbitol, xylitol, mannitol, galactitol,maltitol, hydrogenated isomaltulose (isomalt), lactitol, erythritol,glucitol, ribitol, or a combination thereof; sugar sweeteners generallyinclude saccharides, such as mono-saccharides, di-saccharides andpoly-saccharides such as sucrose (saccharose, sugar), dextrose, maltose,dextrin, maltodextrin, xylose, ribose, glucose (including liquidglucose), mannose, galactose, fructose (levulose), lactose, invertsugar, fructo oligo saccharide syrups, trehalose, tagatose, fucose,gulose, raffinose, ribulose, rufinose, stachyose, xylulose, adonose,amylase, arabinose, deoxyribose, corn syrup solids, such as highfructose corn syrup, or a combination thereof; artificial sweetenerssuch as soluble saccharin salts, i.e., sodium or calcium saccharinsalts, the potassium salt of3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide (Acesulfame-K),the free acid form of saccharin, L-aspartic acid derived sweeteners,such as L-aspartyl-L-phenylalanine methyl ester (Aspartame),L-alphaaspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamidehydrate (Alitame), N-[N-(3,3-dimethylbutyl)-L-aspartyl]-L-phenylalanine1-methyl ester (Neotame), methyl esters of L-aspartyl-L-phenylglycerineand L-aspartyl-L-2,5-dihydrophenyl-glycine,L-aspartyl-2,5-dihydro-L-phenylalanine;L-aspartyl-L-(1-cyclohexen)-alanine, or a combination thereof; maltol;or a combination thereof.

The sweetener can be present in the liquid composition in an amount ofabout 0.1 to about 75 wt % based on the total weight of the liquidcomposition, specifically about 5 to about 50 wt %, and morespecifically about 2.5 to about 25 wt %. The amount of sweetener can bedetermined by one of ordinary skill in the art without undueexperimentation. The use of sensory panels to determine the acceptablesweetness of the liquid composition may be used.

The liquid composition may optionally further comprise a flavoringagent. Flavoring agents include those flavors known to one of ordinaryskill in the art, such as natural flavors and artificial flavors.Suitable amounts of flavoring agent can be selected by one of ordinaryskill in the art without undue experimentation. In one embodiment, theflavoring agent can be present in the liquid composition from about 0.1to about 8.0 wt % based on the total weight of the liquid composition,specifically about 0.4 to about 6 wt %, and more specifically about 1.0to about 3.0 wt %.

The liquid composition can further include a preservative to prevent theunwanted growth of bacteria, molds, fungi, or yeast. Examples ofsuitable preservatives include benzoic acid alkali metal salts (e.g.,sodium benzoate), sorbic acid alkali metal salts (e.g., potassiumsorbate), sodium erythorbate, sodium nitrite, calcium sorbate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), parabens (e.g.,lower alkyl esters of para-hydroxybenzoic acid), alkali metal salts ofparabens including sodium and potassium salts of methyl-, ethyl-,propyl-, or butylparaben, or a combination thereof. Specificpreservatives include sodium methylparaben, sodium propylparaben, andsodium butylparaben.

The preservative can be present in the liquid composition in an amountof about 0.001 to about 0.15 wt % based on the total weight of thecomposition, specifically about 0.0075 to about 0.05 wt %, and yet morespecifically about 0.01 to about 0.04 wt %.

The liquid composition optionally further comprises a colorantconventional in the pharmaceutical art. Colorants can be used in amountseffective to produce a desired color for the composition. The colorantsmay include pigments, natural food colors and dyes suitable forpharmaceutical applications.

The liquid composition optionally further includes a pH adjusting agentto render the final liquid composition to a targeted pH. Suitable pHadjusting agents include pharmaceutically acceptable acids, bases, andtheir salts. Exemplary pH adjusting agents include alkali metalhydroxides (e.g., sodium hydroxide and potassium hydroxide),hydrochloric acid, alkali metal carbonates (e.g., sodium carbonate andpotassium carbonate), carbonic acid, or a combination thereof. The pHadjusting agents can be used as solutions or suspensions in apharmaceutically acceptable solvent. Suitable pharmaceuticallyacceptable solvents for use with the pH adjusting agent can includepurified water, lower alkyl alcohols such as ethanol, a glycol, and thelike, or a combination thereof.

The amount of pH adjusting agent can be any amount to result in adesired pH of the final liquid composition. Such amounts can bedetermined by one having ordinary skill in the art without undueexperimentation.

In another embodiment, the combination of antihistamines is formulatedin a powder form, such as a sachet, to be suspended in a liquid carriersuch as water or saliva. The powder form can be added to a glass ofwater with stirring or taken directly in the mouth where the ingredientsare suspended in saliva. General components in the powder formulationinclude the antihistamines, a sweetener, and a suspending agent;optionally further comprising a flavorant, a colorant, a disintegrant, acombination thereof, and the like.

Solid Dosage Forms

The solid oral dosage form can be a monolithic matrix tablet or alayered tablet having two or more layers wherein the first and thesecond/third antihistamine can be in separate layers or in the samelayer; a capsule; a subunit form such as a plurality of granules,microtablets, minitablets, caplets, pellets (as used herein “pellet”means a spherical granule prepared by extrusion and spheronization, andis equivalent to bead, spheroid, and microsphere), particles, activeagent cores, or other multiparticulate system.

In one embodiment, the first generation antihistamine, the second/thirdgeneration antihistamine, or a combination thereof, is/are formulated asa solid oral dosage form comprising the antihistamine and apharmaceutically acceptable excipient. As used herein, “pharmaceuticallyacceptable excipient” means any other component added to thepharmaceutical formulation other than the active agent. Excipients maybe added to facilitate manufacture, enhance stability, enhance productcharacteristics, enhance bioavailability, enhance patient acceptability,etc. Pharmaceutical excipients include carriers, fillers, binders,disintegrants, lubricants, glidants, granulating agents, compressionaids, colors, sweeteners, preservatives, suspending agents, dispersingagents, film formers, flavorants, printing inks, buffer agents, pHadjusters, preservatives, and the like. In some instances, a singlematerial will meet two or more of the foregoing general classifications.

Exemplary pharmaceutically acceptable excipients include fillers, suchas a water insoluble filler, water soluble filler, or a combinationthereof. The filler may be a water insoluble filler, such as carnaubawax, stearic acid, silicon dioxide, titanium dioxide, talc, alumina,starch, kaolin, polacrilin potassium, powdered cellulose,microcrystalline cellulose, sodium citrate, dicalcium phosphate, or acombination thereof. Exemplary water-soluble fillers include watersoluble sugars and sugar alcohols, specifically lactose, glucose,fructose, sucrose, mannose, dextrose, galactose, the corresponding sugaralcohols and other sugar alcohols, such as mannitol, sorbitol, xylitol,or a combination thereof.

Exemplary binders include alginic acid, a carbomer,carboxymethylcellulose calcium, carboxymethylcellulose sodium,carrageenan, cellulose acetate phthalate, chitosan, ethyl cellulose,guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, microcrystalline cellulose, poloxamer, polyethylene oxide,polymethacrylates, povidone, a saccharide, starch, partiallypregelatinized starch, and the like, or a combination thereof.

Exemplary disintegrants include alginic acid, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, cross-linked sodiumcarboxymethylcellulose (sodium croscarmellose), powdered cellulose,chitosan, croscarmellose sodium, crospovidone, guar gum, low substitutedhydroxypropyl cellulose, methyl cellulose, microcrystalline cellulose,sodium alginate, sodium starch glycolate, partially pregelatinizedstarch, pregelatinized starch, starch, sodium carboxymethyl starch, andthe like, or a combination thereof.

Exemplary lubricants include calcium stearate, magnesium stearate,glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil,light mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate,sodium stearyl fumarate, stearic acid, zinc stearate, or a combinationthereof.

Exemplary glidants include colloidal silica, amorphous silica,precipitated silica, talc, calcium phosphate tribasic, calcium silicate,magnesium silicate, magnesium trisilicate, or a combination thereof.

The solid oral dosage forms can be prepared using equipment andtechniques known in the art for tableting included direct compression,granulation, capsule filling, pelletizing, and the like.

Orally Dispersible Tablet

The antihistamines can be formulated into a non-chewable, orallydisintegrating tablet. These dosage forms can be made by methods knownto those of ordinary skill in the art of pharmaceutical formulations.For example, Cima Labs has produced oral dosage forms includingmicroparticles and effervescents, which rapidly disintegrate in themouth and provide adequate taste-masking. Cima Labs has also produced arapidly dissolving dosage form containing the active agent and a matrixthat includes a nondirect compression filler and a lubricant. U.S. Pat.Nos. 5,178,878 and 6,221,392 provide teachings regarding orallydisintegrating tablets.

An exemplary orally disintegrating tablet includes a mixtureincorporating a water or saliva activated effervescent disintegrationagent and the active agent. The mixture may be formulated as a tablet ofa size and shape adapted for direct oral administration to a patient.The orally disintegrating tablet is substantially completelydisintegrable upon exposure to water or saliva. The effervescentdisintegration agent is present in an amount effective to aid indisintegration of the tablet, and to provide a distinct sensation ofeffervescence when the tablet is placed in the mouth of a patient.

The effervescent sensation is not only pleasant to the patient but alsotends to stimulate saliva production, thereby providing additional waterto aid in further effervescent action. Thus, once the tablet is placedin the patient's mouth, it will disintegrate rapidly and substantiallycompletely without any voluntary action by the patient. Even if thepatient does not chew the tablet, disintegration will proceed rapidly.

The term effervescent disintegration agent includes compounds whichevolve gas. Exemplary effervescent disintegration agents evolve gas bymeans of chemical reactions which take place upon exposure of theeffervescent disintegration agent to water or to saliva in the mouth.The bubble or gas generating reaction is most often the result of thereaction of a soluble acid source and an alkali metal carbonate orcarbonate source. The reaction of these two general classes of compoundsproduces carbon dioxide gas upon contact with water included in saliva.

Such water activated materials may be kept in a generally anhydrousstate with little or no absorbed moisture or in a stable hydrated formsince exposure to water will prematurely disintegrate the tablet. Theacid sources or acid may be those which are safe for human consumptionand may generally include food acids, acid anhydrides and acid salts.Food acids include citric acid, tartaric acid, malic acid, fumaric acid,adipic acid, and succinic acids, etc. Because these acids are directlyingested, their overall solubility in water is less important than itwould be if the effervescent tablet formulations were intended to bedissolved in a glass of water. Acid anhydrides and acid of the abovedescribed acids may also be used. Acid salts may include sodium,dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citratesalts and sodium acid sulfite.

Carbonate sources include dry solid carbonate and bicarbonate salts suchas sodium bicarbonate, sodium carbonate, potassium bicarbonate andpotassium carbonate, magnesium carbonate and sodium sesquicarbonate,sodium glycine carbonate, L-lysine carbonate, arginine carbonate,amorphous calcium carbonate, or a combination thereof.

Where the effervescent agent includes two mutually reactive components,such as an acid source and a carbonate source, in one embodiment bothcomponents react substantially completely. Therefore, an equivalentratio of components which provides for equal equivalents is selected.For example, if the acid used is diprotic, then either twice the amountof a mono-reactive carbonate base, or an equal amount of a di-reactivebase is used for complete neutralization to be realized. However, theamount of either acid or carbonate source may exceed the amount of theother component. This may be useful to enhance taste or performance of atablet containing an overage of either component. In this case, it isacceptable that the additional amount of either component may remainunreacted.

In general, the amount of effervescent disintegration agent useful forthe formation of orally disintegrating tablets is about 5 wt % to about50 wt % based on the total weight of the final dosage form, specificallyabout 15 wt % and about 30 wt %, and more specifically about 20 wt % toabout 25 wt %.

Other types of orally disintegrating tablets can be prepared without aneffervescent agent by using a spray dried carbohydrate or sugar alcoholexcipients=(e.g. sorbitol, mannitol, xylitol, or a combination thereof,and the like), optionally combined with a disintegrant (e.g. thedisintegrant is selected from crospovidone, croscarmellose, sodiumstarch glycolate, pregelatinized starch, partially pregelatinizedstarch, or a combination thereof, and the like), or a glidant (e.g.colloidal silica, silica gel, precipitated silica, or a combinationthereof, and the like). Suitable orally disintegrating tablets can befound in U.S. Patent Application Publication US20030118642 A1 to Normanet al. incorporated herein by reference in its entirety.

Orally disintegrating tablets can be manufactured by well-knowntableting procedures. In common tableting processes, the material whichis to be tableted is deposited into a cavity, and one or more punchmembers are then advanced into the cavity and brought into intimatecontact with the material to be pressed, whereupon compressive force isapplied. The material is thus forced into conformity with the shape ofthe punches and the cavity.

The orally disintegrating tablets typically rapidly disintegrate whenorally administered. By “rapid”, it is understood that the tabletsdisintegrate in the mouth of a patient in less than about 7 minutes, andspecifically between about 30 seconds and about 5 minutes, specificallythe tablet dissolves in the mouth between about 45 seconds and about 2minutes. Disintegration time in the mouth can be measured by observingthe disintegration time of the tablet in water at about 37° C. Thetablet is immersed in the water without forcible agitation. Thedisintegration time is the time from immersion to substantially completedispersion of the tablet as determined by visual observation. As usedherein, the term “complete disintegration” of the tablet does notrequire dissolution or disintegration of the subunits or other discreteinclusions. In one embodiment, disintegration can be determined by USP32 (Test <701>).

Films

In another embodiment, the antihistamines are formulated into an orallydissolving strip, which rapidly dissolves in the mouth to release theactive agent contained in the strip. The orally dissolving stripsgenerally comprise a water soluble polymer and the antihistamines.Exemplary classes of water soluble polymers include water solublecellulosic polymers, water soluble synthetic polymers, water solublenatural gums and polymers or derivatives thereof, or a combinationthereof. Exemplary water soluble cellulosic polymers includehydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose, or a combination thereof. Exemplarywater soluble natural gums and polymers include amylose, dextran,casein, pullulan, gelatin, pectin, agar, carrageenan, xanthan gum,tragacanth, guar gum, acacia gum, arabic gum, sodium alginate, zein, ora combination thereof. Exemplary water soluble synthetic polymersinclude polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone,polyvinyl alcohol, carboxyvinyl polymers, water soluble polyacrylicacid/acrylate, or a combination thereof.

The water soluble polymer may be present in amounts of about 20 to about95 wt %, specifically about 30 to about 85, and more specifically about40 to about 75 wt % based on the total weight of the orally dissolvingstrip.

The orally dissolving strip can further optionally comprise aplasticizer in addition to the water soluble polymer and active agent.Exemplary plasticizers include propylene glycol, glycerin, glycerol,monoacetin, diacetin, triacetin, dimethyl phthalate, diethyl phthalate,dibutyl phthalate, dibutyl sebacate, triethyl titrate, tributyl citrate,triethyl citrate, triethyl acetyl citrate, castor oil, acetylatedmonoglycerides, sorbitol, or a combination thereof. The plasticizer maybe present in amounts of about 0 to about 20, specifically about 1 toabout 15, and more specifically about 5 to about 10 wt % based on thetotal weight of the orally dissolving strip.

The orally dissolving strip can further optionally comprise anemulsifying agent in addition to the water soluble polymer and activeagent. Exemplary emulsifying agents include polyvinyl alcohol, asorbitan esters, a cyclodextrin, benzyl benzoate, glyceryl monostearate,a polyoxyethylene alkyl ether, a polyoxyethylene stearate, poloxamer, apolyoxyethylene castor oil derivative, a hydrogenated vegetable oil, apolysorbate, or a combination thereof.

The emulsifying agent may be present in amounts of about 0 to about 20,specifically about 1 to about 15, and more specifically about 5 to about10 wt % based on the total weight of the orally dissolving strip.

The orally dissolving strip can further optionally comprise a flavorantor sweetener in addition to the water soluble polymer and active agent.Exemplary sweeteners include sugar, a monosaccharide, anoligosaccharide, aldose, ketose, dextrose, maltose, lactose, glucose,fructose, sucrose, a sugar polyol (e.g., mannitol, xylitol, sorbitol,erythritol, and the like), artificial sweeteners (e.g., acesulfamepotassium, sucralose, aspartame, saccharin, sodium saccharin, and thelike) or a combination thereof. The sweetener may be present in amountsof about 0 to about 20, specifically about 1 to about 15, and morespecifically about 5 to about 10 wt % based on the total weight of theorally dissolving strip.

In some embodiments, the orally dissolving formulations of the presentinvention may comprise an additional excipient. Suitable additionalexcipients include, but are not limited to, microcrystalline cellulose,colloidal silicon dioxide, talc, starch, or a combination thereof. Otheroptional components that can be used to prepare the orally dissolvingstrip include a filler/diluent, a surfactant, a disintegrating agent, anantifoaming agent, an antioxidant, a buffering agent, a colorant, or acombination thereof

In one embodiment, the orally dissolving strip exhibits a drug loadingof not more than 50% w/w of the film. Exemplary orally dissolving stripswill comprise about 0.01 to about 50 mg of active agent per strip. Inanother embodiment, the orally dissolving strip has a thickness of about0.1 to about 5.0 millimeters, specifically about 0.3 to about 4.0 andyet more specifically about 0.5 to about 2.5 millimeters. In anotherembodiment the orally dissolving strip has a surface area of about 1.0to about 6.0, specifically about 1.2 to about 4.0 and yet morespecifically about 1.5 to about 2.0 square centimeters.

The orally dissolving strip once placed in the oral cavity may dissolveafter less than about 60 seconds, specifically less than 30 seconds, andyet more specifically less than about 20 seconds.

A solvent can be used in the process to prepare the orally dissolvingstrip, including water, ethanol, 1-butanol, 2-butanol, 2-ethoxyethanol,ethyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone,2-methyl-1-propanol, isobutyl acetate, isopropyl acetate ethyl ether,tert-butylmethyl ether acetone, or a combination thereof. The solvent isused for processing and then removed to result in the final product.

Methods of preparing orally dissolving strips involve solvent castingand film coating. The active agent is mixed with film-forming excipientsand solvents such as water, ethanol, and the like. A thin coating of themixture is cast on a moving, inert substrate and the coated substrate ismoved through a drying oven to evaporate the solvent before die-cuttingthe dried film into strips. Another method involves hot-melt extrusion,by melting an active agent and excipient polymer blend which is thenextruded through a die under molten conditions. The thin film is thencooled to room temperature and die-cut into strips.

Kits

Also included herein are pharmaceutical kits comprising one multipleuse, or a plurality of single use containers or units containing theantihistamine dosage forms as described herein. The kits may furthercomprise one or more conventional pharmaceutical kit components, suchas, for example, one or more containers to aid in facilitatingcompliance with a particular dosage regimen; one or more carriers;printed instructions, either as inserts or as labels, indicatingquantities of the components to be administered, or guidelines foradministration. Exemplary kits can be in the form of bubble or blisterpack cards, optionally arranged in a desired order for a particulardosing regimen. Suitable blister packs that can be arranged in a varietyof configurations to accommodate a particular dosing regimen are wellknown in the art or easily ascertained by one of ordinary skill in theart.

Those forms existing as liquids (e.g solution, emulsion, or suspension)can be packaged for convenient dosing in prepackaged, single usecontainers, or in containers comprising multiple doses.

The combination can be administered to a patient in need of prophylacticand symptomatic treatment of seasonal or perennial allergic rhinitis,vasomotor rhinitis, or other respiratory allergies. Seasonal allergicrhinitis may be due to allergens such as ragweed, grass and treepollens. Perennial allergic rhinitis may be due to allergens such asdust mites, animal dander and molds. Symptoms treated may includesneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocularpruritus, tearing, and redness of the eyes. Patients may include adults,geriatric, or pediatric patients.

The following non-limiting examples further illustrate the variousembodiments described herein.

EXAMPLES Example 1 Immediate Release Tablets/Capsules

Immediate release tablets or capsules are prepared using diphenhydramineHCl as the first antihistamine and fexofenedine HCl as the secondantihistamine. The formulation is provided in Table 1.

TABLE 1 Ingredients Milligram/tablet or capsule Fexofenedine HCl 60.00Diphenhydramine HCl 15.00 PEG 3350 32.50 Croscarmellose Sodium(Ac-Di-Sol) 15.00 Partially pregelatinized maize starch 25.00 (Starch1500 ®) Magnesium Stearate 2.50 Total 150.00

Fexofenedine HCl, diphenhydramine HCl and PEG 3350 are charged into ablender and mixed. Ac-Di-Sol and Starch 1500 are then added to theblender and mixed. Magnesium stearate is passed through a #30 meshscreen and added to the blender and mixed to form a final blend. Thefinal blend can be compressed into tablets or filled into capsules.

One tablet or capsule of Example 1 can be administered to a patienttwice a day.

Example 2 Chewable Tablets

Chewable tablets are prepared using chlorpheneramine maleate as thefirst antihistamine and loratadine as the second antihistamine. Theformulation is provided in Table 2.

TABLE 2 Ingredients Milligram/tablet Loratadine 10.00 ChlorpheneramineMaleate 1.80 Microcrystalline cellulose 38.50 Mannitol 45.00 Silicondioxide 2.00 Citric acid 1.00 Magnesium Stearate 1.00 Aspartame 0.10Color 0.10 Flavor 0.50 Total 100.00

Color is passed through a #30 mesh screen using microcrystallinecellulose. Loratadine, chlorpheneramine maleate, mannitol and thescreened ingredients are charged into a blender and mixed. Silicondioxide, citric acid, aspartame and flavor are passed through a #30 meshscreen and then added to the blender and mixed. Magnesium stearate thathas been screened through a #30 mesh is then added to the blender andmixed to form a final mixture. The final mixture is then compressed intochewable tablets.

One chewable tablet of Example 2 can be administered to a patient once aday.

Example 3 Oral Solution

An oral solution is prepared where each 5 milliliters (ml) contains 1 mgof chlorpheneramine maleate as the first antihistamine and 5 milligramsof cetirizine HCl as the second antihistamine. The oral solutionformulation is shown in Table 3.

TABLE 3 Ingredients Gram/batch Cetirizine HCl 0.10 ChlorpheneramineMaleate 0.02 Citric acid anhydrous, USP/NF 0.30 Glycerin, USP 8.00Propylene glycol 18.38 PEG 400, NF 1.00 Sodium benzoate, NF 0.20 Sugar,NF 20.50 Sodium saccharin 0.30 Soduim citrate, USP/NF 0.40 Color 0.10Flavor 0.20 Purified water 50.50 Total Weight 100.00

The oral solution is prepared by dissolving citric acid and sodiumcitrate in water. Sodium saccharin and sodium benzoate are then addedand dissolved. Cetirizine HCl and chlorpheneramine maleate are thenadded and dissolved by mixing for 10 minutes. Sugar is then added andmixed for 30 minutes to dissolve. Propylene glycol and PEG 400 are thenadded and mixed for 5 minutes. Glycerin is then added and mixed for 10minutes. Colors and flavors are dissolved in a small amount of water andthen added to the main container with mixing. Any remaining water isadded to the mixture and mixed for 25 minutes to form the oral solution.

A 5 milliliter dose of the oral solution of Example 3 can beadministered to a patient as a single daily dose.

Example 4 Orally Disintegrating Tablet

An orally disintegrating tablet is prepared with chlorpheneraminemaleate as the first antihistamine and loratadine as the secondantihistamine (Table 4.).

TABLE 4 Ingredients Milligram/tablet Loratadine 10.00 ChlorpheneramineMaleate 1.80 Granulated mannitol (Pearlitol ® SD100) 70.20 CrosslinkedPolyvinylpyrrolidone (Plasdone XL 10) 10.00 Peppermint flavor 3.00Stearic acid 5.00 Total 100.00

Loratadine, chlorpheneramine maleate and Pearlitol SD100 are chargedinto a blender and mixed. Plasdone XL10 and peppermint flavor are passedthrough a #30 mesh screen and added to the blender and mixed. Stearicacid is passed through a #30 mesh screen, added to the blender and mixedto form a final blend. The final blend is compressed into tablets.

One orally disintegrating tablet of Example 4 can be administered to apatient once a day.

Example 5 Bilayer Tablets

A bilayer tablet is formed having the first antihistaminechlorpheneramine maleate in one layer and second antihistaminecetirizine HCl in a second layer (Table 5).

TABLE 5 Milligram/tablet First Layer Ingredients ChlorpheneramineMaleate 1.80 Microcrystalline cellulose 39.20 Lactose Fast Flo ® 45.00Polyvinylpyrrolidone (Plasdone K29/32) 10.00 CrosslinkedPolyvinylpyrrolidone (Plasdone XL 10) 3.00 Magnesium Stearate 1.00 Total100.00 Second Layer Ingredients Cetirizine HCl 10.00 Microcrystallinecellulose 37.00 Lactose Fast Flo ® 45.00 Silicon dioxide 2.00Croscarmellose Sodium (Ac-Di-Sol) 5.00 Magnesium Stearate 1.00 Total100.00

The first layer is formed by charging chlorpheneramine maleate,microcrystalline cellulose, and Lactose Fastflo into a blender andmixed. Plasdone K29/32 and Plasdone XL10 are passed through a #30 meshscreen, added to the blender and mixed. Magnesium stearate is passedthrough a #30 mesh screen and added to the blender and mixed to form afinal first layer blend.

The second layer is formed by charging cetirizine HCl, microcrystallinecellulose, and Lactose Fastflo into a second blender and mixed. Silicondioxide, and Ac-Di-Sol are passed through a #30 mesh screen, added tothe blender and mixed. Magnesium stearate is then passed through a #30mesh screen, added to the blender and mixed to form a final second layerblend. Bilayer tablets are formed by compressing 100 mg of the finalfirst layer blend and 100 mg of the final second layer blend.

One bilayer tablet of Example 5 can be administered to a patient once aday.

The terms “comprising”, “having”, “including”, and “containing” are tobe construed as open-ended terms (i.e., meaning “including, but notlimited to”). The terms “a” and “an” do not denote a limitation ofquantity, but rather denote the presence of at least one of thereferenced item. The term “or” means “and/or”. The endpoints of allranges directed to the same component or property are inclusive andindependently combinable. The modifier “about” used in connection with aquantity is inclusive of the stated value and has the meaning dictatedby the context (e.g., includes the degree of error associated withmeasurement of the particular quantity). The term “or a combinationthereof” means a combination of one, two, or more of the listed items.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

While the invention has been described with reference to an exemplaryembodiment, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims.

The invention claimed is:
 1. A method of orally administering anantihistamine combination, comprising: concomitantly orallyadministering to an adult human patient in need of antihistaminetreatment a first generation antihistamine in an attenuated dosageamount to provide a quick onset of action wherein the patientexperiences substantially no sedative effect; and a second or thirdgeneration antihistamine in a maintenance dosage amount to providecontinued antihistaminic effect, wherein the administering can occurregardless of the time of day; and wherein the first generationantihistamine is diphenhydramine HCl in an attenuated dosage amount of2.5 mg to 10 mg; or doxylamine succinate in an attenuated dosage amountof 0.625 mg to 4.1 mg.
 2. The method of claim 1, wherein the firstgeneration antihistamine provides therapeutic prophylactic andsymptomatic treatment of seasonal or perennial allergic rhinitis,vasomotor rhinitis, or other respiratory allergies for the first 1 hourafter administration.
 3. The method of claim 1, wherein the firstgeneration antihistamine provides therapeutic prophylactic andsymptomatic treatment of seasonal or perennial allergic rhinitis,vasomotor rhinitis, or other respiratory allergies for the first 2 hoursafter administration.
 4. The method of claim 1, wherein the second orthird generation antihistamine is acrivastine, astemizole, cetirizine,desloratadine, fexofenadine, levocetirizine, loratadine, mizolastine,terfenadine, a pharmaceutically acceptable salt thereof, or acombination thereof.
 5. The method of claim 1, wherein the second orthird generation antihistamine is cetirizine hydrochloride, fexofenadinehydrochloride, loratadine, or a combination thereof.
 6. The method ofclaim 1, wherein the first generation antihistamine and the second orthird generation antihistamine are formulated in a single oral dosageform or in separate oral dosage forms.
 7. The method of claim 6, whereinthe oral dosage form is a tablet, a capsule, a pellet, a film, asolution, a suspension, or an emulsion.
 8. The method of claim 1,wherein the patient is in need of prophylactic or symptomatic treatmentof seasonal or perennial allergic rhinitis, vasomotor rhinitis, or otherrespiratory allergies.
 9. A method of treating a patient in need oftreatment of an allergic reaction, comprising: orally administering toan adult human patient a first generation antihistamine in an attenuateddose to provide a quick onset of action wherein the patient experiencessubstantially no sedative effect; and concomitantly administering orallywith the first generation antihistamine, a second generationantihistamine in a maintenance dose to provide continued antihistaminiceffect, wherein the administering can occur regardless of the time ofday; and wherein the first generation antihistamine is diphenhydramineHCl in an attenuated dosage amount of 2.5 mg to 10 mg; or doxylaminesuccinate in an attenuated dosage amount of 0.625 mg to 4.1 mg.
 10. Themethod of claim 9, wherein the first generation antihistamine providestherapeutic prophylactic and symptomatic treatment of seasonal orperennial allergic rhinitis, vasomotor rhinitis, or other respiratoryallergies for the first 1 hour after administration.
 11. The method ofclaim 9, wherein the first generation antihistamine provides therapeuticprophylactic and symptomatic treatment of seasonal or perennial allergicrhinitis, vasomotor rhinitis, or other respiratory allergies for thefirst 2 hours after administration.
 12. The method of claim 9, whereinthe second or third generation antihistamine is acrivastine, astemizole,cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine,mizolastine, terfenadine, a pharmaceutically acceptable salt thereof, ora combination thereof.
 13. The method of claim 9, wherein the second orthird generation antihistamine is cetirizine hydrochloride, fexofenadinehydrochloride, loratadine, or a combination thereof.
 14. The method ofclaim 9, wherein the first generation antihistamine and the second orthird generation antihistamine are formulated in a single oral dosageform or in separate oral dosage forms.
 15. The method of claim 14,wherein the oral dosage form is a tablet, a capsule, a pellet, a film, asolution, a suspension, or an emulsion.
 16. The method of claim 1,wherein the first generation antihistamine is diphenhydramine HCl in anattenuated dosage amount of 5.0 mg to 6.25 mg; or wherein the firstgeneration antihistamine is Doxylamine Succinate in an attenuated dosageamount of 2.0 mg to 4.1 mg.
 17. The method of claim 9, wherein the firstgeneration antihistamine is diphenhydramine HCl in an attenuated dosageamount of 5.0 mg to 6.25 mg; or wherein the first generationantihistamine is Doxylamine Succinate in an attenuated dosage amount of2.0 mg to 4.1 mg.